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The new paradigm in cancer treatment that aims to inhibit the smoldering inflammatory response in tumors is explored to develop new anticancer treatments. It appears that targeted drug delivery is essential in this concept as high local levels of anti-inflammatory agents are needed to observe the beneficial effects of inflammation inhibition. An overview of classes of anti-inflammatory drugs and drug delivery systems that so far have been studied to treat cancer-inflammation is given. This thesis falls apart in two sections: the first section studies and evaluates the antitumor efficacy of targeted glucocorticoids, whereas the second part focuses on the development and preclinical evaluation of antitumor effects of different anti-inflammatory compounds encapsulated in long-circulating liposomes. In the first section, it is shown that the antitumor effects of liposomal prednisolone phosphate are not limited to tumor-graft models since this potent anti-inflammatory nanomedicine also inhibits tumor growth in a spontaneous mouse tumor model (which more closely resembles the slow progressive chronic inflammatory human disease). When the glucocorticoids is targeted to tumors with core-crosslinked polymeric micelles, the observed antitumor effects do not differ substantially compared to long-circulating liposomes, however the versatility of the polymeric system on drug release profile may assist on the optimization of glucocorticoids release for maximal antitumor effect. In the second section of this thesis, liposomal formulations of different natural (resveratrol, caffeic acid, pterostilbene, carvacrol, etc) or synthetic (pravastatin) anti-inflammatory compounds were developed, characterized and evaluated for antitumor efficacy. Interestingly, only targeted nanomedicines of multi-targeted and potent anti-inflammatory compounds seem to induce antitumor effects in experimental tumor models. The targeted delivery of anti-inflammatory drugs to tumors as anticancer strategy is more complex that foreseen at the outset of these studies and involves several critical factors that have been pinpointed with these studies. Finally, the findings presented in this thesis and suggestions for future work are discussed in a final summarizing discussion.

Natural bioactive compounds have been studied for a long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic. In this study, we examined caffeic acid (derivatives), carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-l-homoserine lactone. These are natural compounds with strong anti-inflammatory properties derived from plants and bacteria. However, these compounds have poor water solubility or are chemically unstable. To overcome these limitations we have prepared liposomal formulations. Our results show that lipophilic 3-oxo-C(12)-homoserine lactone and stilbene derivatives can be loaded into liposomal lipid bilayer with efficiencies of 50-70%. Thereby, the liposomes solubilize these compounds, allowing intravenous administration without use of solvents. When compounds could not be loaded into the lipid bilayer (carvacrol and thymol) or are rapidly extracted from the liposomes in the presence of serum albumin (3-oxo-C(12)-homoserine lactone and pterostilbene derivatives), derivatization of the compound into a water-soluble prodrug was shown to improve loading efficiency and encapsulation stability. The phosphate forms of carvacrol and pterostilbene were loaded into the aqueous interior of the liposomes and encapsulation was unaffected by the presence of serum albumin. Chemical instability of resveratrol was improved by liposome-encapsulation, preventing inactivating cis-trans isomerization. For caffeic acid, liposomal encapsulation did not prevent oxidation into a variety of products. Still, by derivatization into a phenyl ester, the compound could be stably encapsulated without chemical degradation. Despite the instability of liposome-association of 3-oxo-C(12)-homoserine lactone and resveratrol, intravenous administration of these compounds inhibited tumor growth for approximately 70% in a murine tumor model, showing that simple solubilization can have important therapeutic benefits.